The liver is a major organ responsible for the clearance and degradation of immune complexes and foreign antigens; however, despite the presence of functional hepatic antigen presenting cells, humoral and cellular responses to antigens which have entered the portal circulation from the gastrointestinal tract are rare. Moreover, in murine models of autoimmunity multiple cellular abnormalities which may affect immune regulation have been reported including activation of Kupffer cells and high activity of hepatic natural killer cells. Therefore, I plan to investigate specific functional interactions among Kupffer cells, hepatic natural killer, and hepatic accessory cells from autoimmune and nonautoimmune mouse strains. The following hypotheses will be tested: 1) Hepatic accessory cells are functionally different from splenic dendritic cells. Do the hepatic accessory cells preferentially stimulate in a primary immune response Lyt-2 positive suppressor and/or cytotoxic cells? 2) Hepatic natural killer cells are functionally different from splenic NK cells. Are there differences between hepatic and splenic NK cells in target specificity to accessory cells? Do hepatic natural killer cells selectively down-regulate the stimulation of proliferation of suppressor cells? 3) The high hepatic NK activity in the autoimmune strains is secondary to Kupffer cell activation. Is the high NK activity secondary to TNF, interferon, or leukotriene production from Kupffer cells? 4) There are differences in hepatic accessory cell activity between the autoimmune and nonautoimmune strains. Are these differences strain and age-dependent? Are there selective defects in stimulation of Lyt-2 suppressor versus L3T4 helper cells in the hepatic accessory cells of the autoimmune strains? The results of these experiments may help in our understanding of immunoregulation and the autoimmune process in such disease as Juvenile Rheumatoid Arthritis and Systemic Lupus Erythematosus.